PROVIDED. This is the second competing renewal of our Program Project Grant (PPG), entitled, "Signal Transduction and Alzheimer's Disease". This PPG was developed from a program established in the Laboratory of Molecular and Cellular Neuroscience in 1990 for the purpose of investigating the biochemistry, cell biology, molecular biology, and pharmacology of regulation, by protein phosphorylation, of the Alzheimer amyloid precursor protein (APP). Studies of the cellular and molecular mechanisms underlying the sequential cleavage of the APP to B-amyloid (Ap) by Pand y-secretases have afforded great insight into the etiology of Alzheimer's Disease (AD). Understanding the mechanisms that regulate AB generation may enable the development of pharmacologically active compounds that target AB formation. A group of experts in various disciplines of biomedical research will carry out these studies using distinct but complementary approaches. Project 1, entitled "Effects of AB on Synaptic Structure, Transmission and Plasticity", will investigate the effects of Ap on dendritic spine morphology, glutamate receptor trafficking, and long term potentiation in cellular and mouse models of AD. Project 2, entitled "Mechanisms of y- Secretase Regulation" will characterize the underlying mechanism(s) by which ATP, and ATP analogs, including Gleevec, regulate PAPP processing and trafficking. Project 3, entitled "Role of CK1 in Alzheimer Disease Etiology" will evaluate the role of the protein kinase, CK1, in PAPP processing, and identify the targets for CK1 involved in this process. These studies will be supported by a Scientific Core (Core B) that will produce key materials and perform routine, yet critical, tasks that will be required to accomplish the studies described in the other Projects. An Administrative Core (Core A) will coordinate various aspects of the PPG, integrating day-to-day activities of the investigators and consultants involved in the various projects. These studies will lead to greater knowledge of mechanisms involved in the production of AB in the brains of AD patients and will hopefully identify novel proteins that can be targeted by therapeutic agents.